Despite significant efforts cocaine abuse remains a continuing public health problem. Chronic cocaine use is accompanied by neuroadaptations in multiple neurotransmitter systems, as well as enduring changes In brain fundional adivity. To date there are no FDA approved medications for treatment of cocaine dependence. Dmg development efforte are hampered by the lack of underetanding of the neurobiological basis of potential pharmacotherapeutic strategies. The goal of these studies proposed is to characterize at a systems level the neurobiological effecte of potential treatment drugs that have $hown positive signals in cun-ent clinical trials, dmgs approved for use In humans being considered for use in treatment;and mechanistic drug treatments for which preliminary animal studies suggest may be useful in reducing cocaine reinforcement based on their mechanisms of action. The convergence of Information from these different strategies will provide critical Information about the neuropharmacological mechanism of effective treatment and guide foture drug development. Aim 1 will evaluate Uie consequences of chronic administration of candidate medications and tiien assess the neurobiological effeds of these medications in rodent models of chronic cocaine setf-administration in neurochemical systems as established in Project 1 We will measure changes in the fundion of dopamine systems using microdialysis in freely moving rats and voltammetry in brain slices and assess changes in fundional brain adivity with tiie 2-deoxyglucpse method and the expression of immediate eariy genes consequent to chronic treatment with candidate medications. Aim 2 will make use of established nonhuman primate models of cocaine self-administiBtion to evaluate the consequences of these potential pharmacotherapies on brain transmitter systems and to characterize the sites of changes in functional adivity accompanying responses to cocaine-associated cues and cognitive processes as established in Projed 1 It is only through a systems level analysis with clinically relevant models of substance abuse as proposed in this application that a greater understanding of the neurobiological basis of treatnnent can emerge. Thus, ttie systems approach of Projed 2 provides a bridge between behavioral evaluations in Projed 1 and the cellular approaches in Projed 3.